MYC protein is an inherently disordered protein, which lacks a hydrophobic pocket or groove suitable for binding small molecule compounds. Currently, no small molecule compounds that can bind MYC have been found. At the same time, since MYC is located in the cell nucleus, it is difficult to target it with macromolecules such as monoclonal antibodies. Therefore, indirect targeting of MYC becomes an effective and feasible alternative therapeutic strategy. In this article, according to their function mechanisms, the current small molecule compounds indirectly targeting MYC are divided into two categories: inhibitors acting on MYC PPI (protein-protein interaction) and target inhibitors regulating MYC action. Some compounds of different mechanisms are introduced and reviewed, hoping to provide a reference for cancer therapy targeting MYC.
MYC PPI Inhibitors
At present, many small molecules regulating protein-protein interactions have been found through high-throughput virtual screening or in vitro screening strategies. They are divided into three classes: MYC-MAX heterodimer inhibitors, MAX-MAX homodimer stabilizers, and MYC-MAX-DNA binding regulators.
MYC-MAX heterodimer inhibitors are small molecules that can directly disrupt the heterodimerization process of MYC-MAX, which can make MYC’s inherently disordered b-HLH-LZ domain become no longer disordered and promote its transformation into a more rigid and well-defined domain, thus preventing its recognition of MAX proteins. As for the MAX-MAX homodimers, after being stabilized, they can reduce the heterodimerization of MYC with MAX, thus preventing MYC-MAX transactivation of the target gene. Researchers have also found that when MYC and MAX heterodimerize, the compound will adopt a stable helical configuration, which can bind specific DNA recognition sequence 5′-CACGTG-3′(E-Box) at the enhancer and promoter of target genes, thus triggering the collection of chromatin remodeling complexes and assembly of the transcription mechanism, then driving the transcription process.
Inhibitors Regulating MYC Function
Multiple studies have shown that MYC can also be indirectly targeted by inhibiting its regulatory targets, such as inhibiting the BET family of proteins (BRDs) or stabilizing the structure of MYC G4. In recent years, the two targeting strategies have been extensively developed with several small molecule drugs entering the clinic phase.
The BET inhibitor ABBV-744 can selectively inhibit the BRD4 BD2 protein and is currently in phase I clinical trials for the treatment of acute myeloid leukemia. Besides, many natural compounds have been reported to stabilize the G4 structure and inhibit MYC expression, such as fonsecin B, alkaloids, piperine, and quercetin. Nevertheless, the synthetic small molecules demonstrate a better binding affinity and specificity for MYC G4. For instance, in 2018, Calabrese et al. screened a trifluoromethyl substituted compound from the benzofuran derivative library, which has a strong affinity for MYC G4 and can effectively down-regulate the expression of MYC gene in multiple myeloma cells. Unlike other G4 stabilizer compounds, this compound does not bind dsDNA and shows a weak affinity for the G4 structure of other oncogenes, showing certain selectivity.
Although many achievements have been made in inhibitors regulating MYC function, researchers are also confronted with some problems. BET inhibitors have poor selectivity and subsequent adverse drug reactions. Early clinical trials about G4 stabilizers have also shown that small molecule stabilizers designed based on the structural characteristics of DNA and RNA have difficulties in specifically interacting with individual G4. All the above issues should be attached to great attention in the future R&D of MYC small molecule inhibitors.
Conclusion
This article summarizes the research progress of targeted MYC small molecule inhibitors, which offers a partial reference for related pharmaceutical chemists. Hopefully, more research works and achievements can be reported in the future and more follow-up small molecules can move to clinical trials or into the market, which can certainly benefit a large number of patients.
Related Tags:
| Tag | Description |
| MYC | Indirect targeting of MYC becomes an effective and feasible alternative therapeutic strategy. |
| BET Bromodomain | BET bromodomain inhibitors, which have shown efficacy in several models of cancer. |
| Alkaloids | Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. |
Related Products:
| Name | CAS | Description |
| ABBV-744 | 2138861-99-9 | ABBV-744 is a BDII-selective BET bromodomain inhibitor, developed for the treatment of AML and cancer. |
| Piperine | 94-62-2 | Piperine is an alkaloid isolated from black pepper that is used in some traditional medicines. |
| Quercetin | 117-39-5 | Quercetin is a flavonoid found in galangal and is used as an antitumor agent that induces apoptosis of cancer cells. |